High level expression of the genes encoding some of these exporters in both prokaryotic and eukaryotic organisms (including human) result in the development of resistance to multiple drugs such as antibiotics and anti-cancer agents.

For instance, a potential lethal increase in osmotic strength is counterbalanced by activation of osmosensing ABC transporters that mediate uptake of solutes.

It is found to mediate the secretion of the steroid aldosterone by the adrenals, and its inhibition blocked the migration of dendritic immune cells,[19] possibly related to the outward transport of the lipid platelet activating factor (PAF).

MDR1 can also transport cholesterol, short-chain and long-chain analogs of phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), sphingomyelin (SM), and glucosylceramide (GlcCer).

After the ATP powered move to the outward facing conformation, molecules are released from the binding site and allowed to escape into the exoplasmic leaflet or directly into the extracellular medium.

Importers have an inverted organization, that is, NBD-TMD-NBD-TMD, where the ABC domain is N-terminal whereas the TMD is C-terminal, such as in the E. coli MacB protein responsible for macrolide resistance.

Four individual polypeptide chains including two TMD and two NBD subunits, may combine to form a full transporter such as in the E. coli BtuCD[24][25] importer involved in the uptake of vitamin B12.

[29] In the MetI transporter, a minimal set of 5 transmembrane helices constitute this fold while an additional helix is present for both ModB and MalG.

The type II ABC importer fold is observed in the twenty TM helix-domain of BtuCD[24] and in Hi1471,[30] a homologous transporter from Haemophilus influenzae.

[35] These structures were also consistent with results from biochemical studies revealing that ATP is in close contact with residues in the P-loop and LSGGQ motif during catalysis.

These proteins harness the energy of ATP binding and/or hydrolysis to drive conformational changes in the transmembrane domain (TMD) and consequently transport molecules.

Spectroscopic, protease accessibility and crosslinking studies have shown that ATP binding to the NBDs induces conformational changes in multidrug resistance-associated protein-1 (MRP1),[59] HisPMQ,[60] LmrA,[61] and Pgp.

ATP binding induces a rigid body rotation of the two ABC subdomains with respect to each other, which allows the proper alignment of the nucleotide in the active site and interaction with the designated motifs.

[52] Most ABC transporters that mediate the uptake of nutrients and other molecules in bacteria rely on a high-affinity solute binding protein (BP).

The structures provided detailed pictures of the interaction of the transmembrane and ABC domains as well as revealed two different conformations with an opening in two opposite directions.

This portion of the EAA loop docks in a surface cleft formed between the RecA-like and helical ABC subdomains and lies approximately parallel to the membrane bilayer.

The resting state of importers is inward-facing, where the nucleotide binding domain (NBD) dimer interface is held open by the TMDs and facing outward but occluded from the cytoplasm.

[65] In gram-negative organisms, ABC transporters mediate secretion of protein substrates across inner and outer membranes simultaneously without passing through the periplasm.

A central pore, which is enclosed between the TMDs, is slightly open towards the intracellular face with a gap between two domains allowing access of substrate from the lipid phase.

Plant ABC proteins are categorized in 13 subfamilies on the basis of size (full, half or quarter), orientation, and overall amino acid sequence similarity.

[68] Plant ABCB transporters are characterized by heterologously expressing them in Escherichia coli, Saccharomyces cerevisiae, Schizosaccharomyces pombe (fission yeast), and HeLa cells to determine substrate specificity.

The ADP-bound structure of Sav1866 shows the NBDs in a closed dimer and the TM helices split into two "wings" oriented towards the periplasm, forming the outward-facing conformation.

[41] The resting state of E. coli MsbA exhibits an inverted "V" shape with a chamber accessible to the interior of the transporter suggesting an open, inward-facing conformation.

In the closed apo state (from V. cholerae MsbA), the NBDs are aligned and although closer, have not formed an ATP sandwich, and the P loops of opposing monomers are positioned next to one another.

The NBDs in this nucleotide-bound, outward-facing conformation, come together to form a canonical ATP dimer sandwich, that is, the nucleotide is situated in between the P-loop and LSGGQ motif.

Thus, changes in both the orientation and spacing of the NBDs dramatically rearrange the packing of transmembrane helices and effectively switch access to the chamber from the inner to the outer leaflet of the membrane.

Hydrolysis of the second ATP molecule and release of Pi separates the NBDs followed by restoration of the resting state, opening the chamber towards the cytoplasm for another cycle.

Inhibition of ABC transporters by low-molecular weight compounds has been extensively investigated in cancer patients; however, the clinical results have been disappointing.

ABCD1 is responsible for the X-linked form of Adrenoleukodystrophy (ALD) which is a disease characterized by neurodegeneration and adrenal deficiency that typically is initiated in late childhood.

The cells of ALD patients feature accumulation of unbranched saturated fatty acids, but the exact role of ABCD1 in the process is still undetermined.